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| United States Patent |
5,079,364
|
|
Temperilli
, et al.
|
January 7, 1992
|
t-alkyl ergoline derivatives
Abstract
t-alkyl eroline derivatives of formula I are produced
##STR1##
wherein (R.sub.1 =H, OCH.sub.3 and R.sub.2 H) or (R.sub.1 +R.sub.2 =a ring
bond and R.sub.3 =H, optionally substituted nicotinynoyl or
1-oxo-2-cyclopenten-3-yl); and their pharmaceutically acceptable salts.
A process for the preparation of these derivatives from lysergol and a
t-alkyl alcohol is also described, as are pharmaceutical compositions
containing them.
| Inventors:
|
Temperilli; Aldemio (Milan, IT);
Brambilla; Enzo (Comense, IT);
Gobbini; Mauro (Sesto Calende, IT);
Cervini; Maria A. (Cardano Al Camp, IT)
|
| Assignee:
|
Farmitalia Carlo Erba (Milan, IT)
|
| Appl. No.:
|
328518 |
| Filed:
|
March 24, 1989 |
Foreign Application Priority Data
| Current U.S. Class: |
546/68 |
| Intern'l Class: |
C07D 457/09 |
| Field of Search: |
546/67,68
514/288
|
References Cited
U.S. Patent Documents
| Re30218 | Feb., 1980 | Bach et al. | 546/67.
|
| 3232942 | Feb., 1966 | Hofmann et al. | 546/67.
|
| 3959288 | May., 1976 | Bach et al. | 546/67.
|
| 4197299 | Apr., 1980 | Ferrari et al. | 546/67.
|
| Foreign Patent Documents |
| 0171988 | Feb., 1986 | EP.
| |
| 3403067 | Aug., 1985 | DE | 546/67.
|
Other References
Morrison and Boyd, Organic Chemistry, [Boston: Allyn and Bacon, 1980] p.
82.
|
Primary Examiner: Shah; Mukund J.
Assistant Examiner: Ward; E. C.
Attorney, Agent or Firm: Oblon, Spivak, McClelland, Maier & Neustadt
Parent Case Text
This is a division of application Ser. No. 07/065,597, filed June 23, 1987,
now U.S. Pat. No. 4,843,073.
Claims
What is claimed as new and desired to be secured by Letters Patent of the
United States is:
1. 1-(t-butyl)-10-methoxy-6-methyl-8.beta.-hydroxymethyl-ergoline.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to ergoline derivatives, to processes for their
preparation and to pharmaceutical compositions containing ergoline
derivatives.
2. Discussion of the Background
The 1-alkylation of ergolines may be performed by reacting non-alkylated
ergolines with alkyl halides in liquid ammonia in the presence of a strong
base such as potassium amide (see Troxler F., Hofmann A., Helv. Chim.
Acta, 40 2160 (1957)). The efficiency of this alkylation reaction is good
for primary alkyl halides, but much reduced for secondary alkyl halides.
Tertiary alkyl halides do not react at all but instead yield the related
olefins by elimination.
The prior art has not disclosed a suitable methodology for the addition of
a tertiary alkyl group to the 1 position of the ergoline molecule.
SUMMARY OF THE INVENTION
One object of this invention is to provide processes for the preparation of
1-tertiaryalkyl ergoline derivatives, for example, 1-t-butyl ergoline
derivatives.
Another object of this invention is to provide 1-tertiaryalkyl ergoline
derivatives, for example, 1-t-butyl ergoline derivatives, which are useful
as therapeutic agents.
Another object of this invention is to provide pharmaceutical compositions
containing such ergoline derivatives.
These and other objects as will hereinafter become more clear from the
following disclosure have been attained by preparing
1-(tertiaryalkyl)-ergoline derivatives, e.g. 1-t-butyl ergoline, by using
a tertiary alcohol, e.g., t-butanol in trifluoroacetic anhydride, under
conditions that one would have expected to lead to electrophilic bonding
to position 2 of the ergoline ring or in the aromatic ring. This results
in the production of an ergoline derivative of the formula
##STR2##
wherein: R.sub.1 and R.sub.2 taken together represent a ring bond; or
R.sub.1 is a hydrogen atom or a methoxy group and R.sub.2 is a hydrogen
atom; or
R.sub.3 is a hydrogen atom, a nicotinoyl group, a substituted nicotinoyl
group, or a 1-oxo-2-cyclopenten3-yl group; R.sub.4 is a C.sub.1 -C.sub.4
alkyl; or
a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Lysergol (II) can be t-alkylated, e.g., t-butylated, at position 1 of the
ergoline skeleton by reacting ergoline with tertiary alcohol, e.g.,
t-butanol, in trifluorcacetic anhydride for a period of from 70 to 90
hours at a temperature between 15.degree.-30.degree. C. and, preferably
between 20.degree.-25.degree. C. This reaction may be carried out in the
presence or absence of other organic solvents, such as benzene, DMF or
dioxane.
##STR3##
wherein R.sub.1 and R.sub.2 taken together represent a ring bond, and
R.sub.3 represents a hydrogen atom and R.sub.4 is independently a C.sub.1
-C.sub.4 alkyl, preferably methyl.
The tertiary alkyl lysergol, e.g., t-butyl-lysergol. so obtained may be
transformed into a 10-methoxy derivative, according to the process of U.S.
Pat. No. 3,647,655 or reduced to the dihydro derivative by reduction with
hydrogen in the presence of a noble metal.
The ergoline derivatives of the present invention have the formula I
##STR4##
wherein either R.sub.1 represents a hydrogen atom or a methoxy group and
R.sub.2 represents a hydrogen atom or R.sub.1 and R.sub.2 taken together
form a ring bond, and R.sub.3 represents a hydrogen atom, a nicotinoyl or
substituted nicotinoyl group or a 1-oxo-2-cyclopenten-3-yl group; and
further provides pharmaceutically acceptable salts of such ergoline
derivatives. When R.sub.3 represents a substituted nicotinoyl group, the
substituent is preferably an alkyl group having from to 4 carbon atoms, a
nitro, cyano, hydroxy, amino or aminomethyl group, or a halogen atom such
as a bromine atom. R.sub.4 is independently a C.sub.1-4 alkyl group,
preferably methyl, such that (R.sub.4).sub.3 C is a t-alkyl group.
1-(t-butyl)-10-methoxy-6-methyl-8.beta.-hydroxymethylergoline,
1-(t-butyl)-10-methoxy-6-methyl-8.beta.-(5-bromo-3-pyridine-carboxymethyl)
-ergoline and 1-(t-butyl)-10-methoxy-
6-methyl-6.beta.-(1-oxo-2-cyclopenten-3-yloxymethyl)ergoline are some of
the preferred compounds of the invention.
The compounds of the invention may be administered in the form of a
pharmaceutically acceptable acid addition salt. Such salt forms have the
same order of activity as the free base forms.
The tertiary alkyl ergoline derivatives of the invention may be produced by
reacting lysergol with an excess quantity of a tertiary alkyl alcohol,
e.g., t-butanol, in the presence of a catalytic amount of trifluroacetic
anhydride, in the presence or absence of an inert organic solvent, at a
temperature between 15.degree. and 30.degree. C. for 70 to 90 hours,
preferably at 20-25.degree. C. for 70-90 hours.
The 1-tertiary alkylated lysergol is then either hydrogenated in the
presence of a noble metal catalyst, or alkoxylated upon UV irradiation in
the presence of an alcohol and sulfuric acid, to form a
1-tertiaryalkylergoline derivative.
The compounds of the general formula I wherein R.sub.3 represents a
hydrogen atom may be converted into other compounds of the general formula
I using normal chemical reactions. For example the esterification of the
C-17 hydroxy group is effected by treatment with the anhydride or chloride
of an organic acid in the optional presence of a tertiary amine such as
pyridine, triethylamine and the like, according to the method described in
U.S. Pat. No. 3,228,943 (incorporated by reference herein). The
etherification is effected by treatment of the corresponding tosyl esters
with 1,3-dicarbonyl compounds in sodium salt form in
hexamethylphosphotriamide as solvent as described in U.S. Pat. No.
4,382,940 (incorporated by reference herein). Preferably, this
etherification is carried out by reaction with 1,3-cyclopentendione for
2-4 hours at a temperature between 70.degree. C.-100.degree. C.
It has been found that the presence of a t-butyl group in the position 1 of
the ergoline skeleton is advantageous in comparison to the presence of a
methyl group (U.S. Pat. No. 3,879,554) as shown by electroencephalographic
effects (EEG) which show increased and longer-lasting modifications in
terms of cortical activation. These modifications suggest the clinical
usefulness of these derivatives for the following conditions: diffuse
cerebral arteriosclerosis, transient cerebral ischemia and involution
syndromes of presenile age, senescence and senility (Buonamici, M., Young,
G. A. and Khazan (1982) Neuropharmacology 21 : 825-829, "Effects of Acute
.DELTA..sup.9 -THC Administration on EEG and EEG Power Spectra in the
Rat").
In this test the compounds were administered at doses of 5-10-20 mg/kg p.o.
to groups of 8 rats.
The oral orientative acute toxicity (LD.sub.50) of the compounds of the
formula I was higher than 800 mg/kg.
The compounds are therefore useful in the treatment of cerebral
insufficiency and senile dementia, particularly the early stages thereof.
For this use the dosage will, of course, vary depending on the compound
employed, mode of administration and treatment desired. However, in
general, satisfactory results are obtained when administered at a daily
dosage of from 0.001 mg to about 50 mg per kg animal body weight,
conveniently given in divided doses 2 to 4 times a day or in sustained
release form. For the larger mammal, the total daily dosage is in the
range of from 1 to about 100, preferably 10 to 90 mg, and dosage forms
suitable for oral administration comprise from about 0.2 mg to about 50 mg
of the compounds admixed with a solid or liquid pharmaceutically
acceptable carrier or diluent, such as starch, lactose, dextrin, magnesium
stearate or water.
The present invention accordingly provides a pharmaceutical composition
comprising at least one ergoline derivative I as herein defined or a
pharmaceutically acceptable salt thereof in admixture with a
pharmaceutically acceptable diluent or carrier. Such compositions may be
formulated in a conventional manner so as to be, for example, a solution
or a tablet. The compounds of the present invention may be used in an
analogous manner to standard compounds used for the indications mentioned
above.
Other features of the invention will become apparent in the course of the
following descriptions of exemplary embodiments which are given for
illustration of the invention and are not intended to be limiting thereof.
EXAMPLE 1
1-(t-Butyl)-9,10-didehydro-6-methyl-8.beta.-hydroxymethylergoline
To a mixture of 8 g of lysergol in 150 ml of t-butanol, 200 ml of
trifluoroacetic anhydride were added dropwise with vigorous stirring.
After the solution had been left at room temperature for 90 hours, it was
evaporated. The residue was dissolved in water, made alkaline with
ammonium hydroxide and the aqueous layer was extracted with ethyl acetate.
After removal of the ethyl acetate, the residue was purified by silica gel
column chromatography using 1:1 cyclohexane:ethyl acetate for elution to
give 6 g of the title compound melting at 181 to 183.degree. C.
EXAMPLE 2
1-(t-Butyl)-10-methoxy-6-methyl-8.beta.-hydroxymethylergoline
A solution of 6 g of
1-(t-butyl)-9,10-didehydro-6-methyl-8.beta.-hydroxymethyl-ergoline,
prepared as described in Example 1, in 500 ml of methanol and 5 ml of
sulphuric acid was irradiated at 20.degree. C. in a Pyrex flask with a
Hanau PL 321 lamp for about 6 hours, until the absorption at 315 nm
completely disappeared. The solution was diluted with iced water, made
basic with ammonium hydroxide, evaporated to 100 ml and extracted with
ethyl acetate. After evaporation of the solvent the residue was
chromatographed in silica gel and on elution with 97:3
dichloromethane:methanol, 5 g of the title compound was isolated, m.p. 172
to 174.degree. C. from acetone.
EXAMPLE 3
1(t-Butyl)-10-methoxy-6-methyl-8.beta.-(5-bromo-3-pyridinecarboxymethyl)-er
goline
2.65 g of 5-bromonicotinoyl chloride were added at 25.degree. C. to a
solution of 3 9 of
1-(t-butyl)-10-methoxy-6-methyl-8.beta.-hydroxymethyl-ergoline prepared as
described in Example 2, in 35 ml of pyridine. After 4 hours the solution
was evaporated in vacuo, the residue was taken up in water containing
ammonium hydroxide and extracted with dichloromethane. Evaporation of the
solvent left a residue that was purified by chromatography over silica gel
using cyclohexane with increasing amounts of acetone (from 0 to 30
percent) as the eluant, to give 4 g of the title compound melting at 75 to
77.degree. C.
EXAMPLE 4
1-(t-Butyl)-10-methoxy-6-methyl-8.beta.-(1-oxo-2-cyclopenten-3-yloxymethyl)
-ergoline
a) To a solution of 1.8 g of
1-(t-butyl)-10-methoxy-6-methyl-8.beta.-hydroxymethyl-ergoline, prepared
as described in Example 2,.in 20 ml of pyridine, 2.8 g of tosyl chloride
in 15 ml of pyridine were slowly added. After the addition had been
completed, the mixture was stirred for about six hours and was then poured
into cold water and extracted with dichloromethane. The organic layer was
evaporated off and the residue was chromatographed over 18 g of silica gel
using dichloromethane with increasing amounts of methanol (from 0 to 4
percent) as the eluant. 2 g of
1-(t-butyl)-10-methoxy-6-methyl-8.beta.-tosyloxymethyl-ergoline were
obtained, melting at about 150 to 152.degree. C.
b) A mixture of 2 g of the compound prepared in the first part of this
Example and 0.7 g of 1,3-cyclopentandione sodium salt in 15 ml of
hexamethylphosphotriamide was heated at 80.degree. C. for 3 hours. The
resulting solution was poured into 200 ml of water and the suspension was
extracted with ethyl acetate. After evaporation of the organic solvent the
residue was purified by crystallization from diethyl ether to give 1.5 g
of the title compound, m.p. 145 to 147.degree. C.
EXAMPLE 5
1-(t-Butyl-6-methyl-88-hydroxymethyl-ergoline
A solution of 4 g of
1-(t-butyl)-9,10-didehydro-6-methyl-8.beta.-hydroxymethyl-ergoline,
prepared as described in Example 1, in 500 ml of methanol was hydrogenated
in the presence of 4 g of 10% palladium on carbon catalyst. After removing
the catalyst by filtration and the methanol by evaporation, the residue
was crystallized from water:methanol to give 3 g of the title compound
melting at 162 to 164.degree. C.
Obviously, numerous modifications and variations of the present invention
are possible in light of the above teachings. It is therefore to be
understood that within the scope of the appended claims, the invention may
be practiced otherwise than as specifically described herein.
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